Brainstem Infiltration Predicts Survival in Patients With High-grade Gliomas Treated With Chemoradiotherapy.

BACKGROUND/AIM: High-grade gliomas have a poor prognosis despite standard treatment. The aim of the study was to identify new prognostic factors to select patients who need more intense treatment. PATIENTS AND METHODS: Forty-three consecutive patients underwent surgery plus chemoradiotherapy for pathologically diagnosed high-grade gliomas (grade III, IV). RESULTS: The median survival time was 989 days, and the 1-year survival rate was 87.6%. Among patients with grade IV disease, the median survival time, 1-year, and 2-year survival rate were 814 days, 82.6%, and 58.7%, respectively. In the univariate analysis, unmethylated MGMT promoter (p=0.0495), brainstem infiltration (p=0.0004), basal ganglia as the primary lesion site (p=0.0056), 3-dimensional conformal radiotherapy (p=0.0286), and <50 Gy (p=0.0049) were associated with a poor prognosis. In the multivariate analysis, only brainstem infiltration retained significance (HR for death, 0.21; 95% CI=0.06-0.70; p=0.011). CONCLUSION: Brainstem infiltration is a novel prognostic factor for poor prognosis in patients with high-grade gliomas.

Balloon-Assisted Embolization of Wide-Neck Aneurysms Using a Mixture of n-Butyl Cyanoacrylate, Lipiodol, and Ethanol in Swine: A Comparison of Four n-Butyl Cyanoacrylate Concentrations.

PURPOSE: To determine the optimal ratio of n-butyl cyanoacrylate (NBCA)-Lipiodol-ethanol (NLE) mixture for balloon-assisted embolization of wide-neck aneurysms. MATERIALS AND METHODS: We created 32 wide-neck aneurysms on both the common carotid arteries and external iliac arteries in eight female swine. Eight aneurysms were randomly assigned to four groups. Under balloon occlusion, the aneurysms were packed using NLE at one of four ratios of NLE: 2:2:1 (NLE221; 40%NBCA); 3:6:1 (NLE361; 30%NBCA); 2:7:1 (NLE271; 20%NBCA); and 1:5:1 (NLE151; 14.3%NBCA). We performed angiography before and after embolization to assess the aneurysms, and we compared adhesion between NLE and the balloon and assessed NLE migration. Three days after embolization, the aneurysms were removed for histopathologic evaluation. RESULTS: Embolization was performed in 27 aneurysms. Adhesion between NLE and the balloon was not observed in any group. NLE migration was found in 0/7 aneurysms in the NLE221 group, 0/6 in the NLE361 group, 5/6 in the NLE271 group, and 7/8 in the NLE151 group. NLE migration was significantly lower in the NLE221 group than in the NLE271 and NLE151 groups (P = 0.0047 and 0.0014, respectively) and was significantly lower in the NLE361 group than in the NLE271 and NLE151 groups (P = 0.0152 and 0.0047, respectively). Media necrosis of the arterial wall close to the aneurysms was observed in all groups. CONCLUSION: NLE with an NBCA concentration of ≥ 30% is a safe and feasible embolic material for balloon-assisted embolization of wide-neck aneurysms in swine in the short term up to 3 days after embolization.

Exaggerated arsenic nephrotoxicity in female mice through estrogen-dependent impairments in the autophagic flux.

Gender is one of the essential factors in the development of various diseases and poisoning. Therefore, we herein examined gender differences in sodium arsenite (NaAsO2)-induced acute renal dysfunction. When male and female BALB/c mice were subcutaneously injected with NaAsO2 (12.5mg/kg), serum and urinary markers for proximal tubular injury were significantly higher in female mice than in male ones. NaAsO2-induced histopathological alterations were consistently more evident in females than in males. Ovariectomy, but not orchiectomy significantly attenuated NaAsO2-induced renal injury. These results imply that the hypersusceptibility of female mice is attributed to estrogen signals. NaAsO2 suppressed the autophagic flux in tubular cells through the activation of ERK. Enhancements in the activation of ERK were significantly greater in females than in males, with the eventual accumulation of LC3-II and P62 in the kidneys, implying that the autophagic flux is impaired in females. The IL-6/STAT3 signaling pathway had protective roles in NaAsO2-induced nephrotoxicity through the suppression of ERK activation. Despite the absence of differences in intrarenal IL-6 expression between male and female mice, STAT3 was less activated with enhanced SOCS3 expression in females than in males. An in vitro study using mProx24 cells revealed that the estrogen treatment induced SOCS3 expression, and eventually suppressed the autophagic flux, as evidenced by greater increases in the accumulation of LC3-II and p62 with ERK activation, which was canceled by the knockdown of Socs3. Collectively, these results indicate that estrogen has a negative impact on the development of NaAsO2 nephrotoxicity through its suppression of the autophagic flux.

Immunohistochemical analysis on MMP-2 and MMP-9 for wound age determination.

We performed immunohistochemical study combined with morphometrical analyses in order to examine the expression of matrix metalloproteinase-2 (MMP-2) and MMP-9 using 55 human skin wounds of different ages: group I, 0-3 days (n = 16); II, 4-7 days (n = 11); III, 9-14 days (n = 16); and IV, 17-21 days (n = 12). Immunopositive reactions for MMP-2 were observed in all human skin specimens including uninjured skin as control. The number of MMP-2(+) macrophages was significantly increased in accordance with wound ages. In contrast to MMP-2, no MMP-9(+) signals were detected in uninjured and wound specimens aged less than 1 day. However, the number of MMP-9(+) macrophages profoundly appeared in groups II and III. Morphometrically, in all of wound samples aged 9-12 days, MMP-2(+) cell number was more than 20. On the contrary, most of the remaining samples had <20 positive cells. However, only one sample (a 7-day-old wound) showed 21 positive cells. Thus, with regard to practical applicability with forensic safety, MMP-2(+) macrophages of >20 would indicate a wound age of 7-12 days. Additionally, 10 out of 12 wound specimens aged 9-12 days showed the MMP-2(+) cell number of >25, implying that MMP-2(+) cell number of >25 would indicate the wound age of 9-12 days. On the contrary, all wound samples aged 3-14 days except for only one sample had MMP-9(+) cell number of >30, indicating that MMP-9(+) cell number of >30 would indicate the wound age of 3-14 days. Collectively, MMP-2 seemed to be more distinct marker, compared with MMP-9.

Autophagy in skin wounds: a novel marker for vital reactions.

Detection of vitality of mechanical wounds in human cadavers is one of the important issues in forensic medicine. In order to explore novel markers for vitality of acute mechanical wounds, we investigated autophagy in mouse and human skin wounds. Western blotting analysis of mouse skin wounds showed marked reduction of LC3-II and reciprocal increase of p62 in wound samples with the postinfliction intervals of ≥0.5 h, compared with the uninjured skin tissues. These observations indicated that autophagy level was reduced in the wound sites. In postmortem wound samples, there were no remarkable changes in LC3-II and p62 levels. Furthermore, the postmortem intervals of 1-4 days have no significant effects on the changes of LC3-II and p62 in the antemortem skin wounds. Like murine wound samples, these alterations of LC3-II and p62 could be detected in human skin wound samples. Collectively, our study using animal and human samples implied that the detection of autophagy-related molecules such as LC3-II and p62 might be useful for forensic practice as markers of wound vitality.

Immunohistochemical detection of intrathrombotic IL-6 and its application to thrombus age estimation.

We immunohistochemically examined intrathrombotic IL-6 expression using a murine model of deep vein thrombosis induced by the ligation of the inferior vena cava (IVC) and discussed the availability of intrathrombotic IL-6 for thrombus age estimation. IL-6(+) cells could be first detected at 1 day after IVC ligation in three of five samples, and all samples with postligation intervals of 3 days or more had intrathrombotic IL-6(+) cells. Thereafter, the numbers of IL-6(+) cells were elevated with the increase of postligation intervals. Double-color immunofluorescence analyses demonstrated that IL-6 was mainly expressed by intrathrombotic macrophages. In all samples with postligation intervals of 5 days or less, the IL-6/macrophage ratio (IL-6/Mϕ) was <0.5. In contrast, the IL-6/Mϕ was greater than 0.5 at ≥7 days after the IVC ligation. These observations implied that IL-6/Mϕ ratios of >0.5 would strongly indicate thrombus ages of ≥7 days. Reciprocally, the ratios of less than 0.5 would suggest thrombus ages of ≤5 days. The present study demonstrated that the immunohistochemical detection of IL-6 was suitable to estimate the age of venous thrombi.

Sudden unexpected neonatal death due to late onset group B streptococcal sepsis--a case report.

We report a case of sudden unexpected death due to late onset neonatal group B streptococcal sepsis. A male neonate weighing 2731g was born at 35week gestational age, and discharged at the age of 4days after the birth. At 6days after the discharge (10days after the birth), because of consciousness loss and hypothermia, the neonate was conveyed to an emergency hospital, eventually followed by his death. Forensic autopsy revealed neither severe trauma nor cardiac anomaly. Both lungs were edematous. Histopathologically, a lot of bacterial clusters were found in the lungs and intracerebral vessels. Cerebrospinal fluid contained a lot of leukocytes. Streptococcus agalactiae was detected in the specimens from the feces and the blood. Collectively, we diagnosed that the cause of the neonate's death was late onset group B streptococcal sepsis. In autopsy cases of neonates, careful macroscopic and microscopic observations and bacteriological/virological examination should be performed.